Impaired endothelial cell-derived CX3CL1-mediated macrophage efferocytosis in hypertrophic cardiomyopathy based on multi-omics analysis.

IF 5.4 3区医学 Q2 CELL BIOLOGY

Inflammation Research Pub Date : 2025-08-05 DOI:10.1007/s00011-025-02075-8

Yan Zhang, Xin Yan, Xiao-Lei Fu, Hai-Bing Yang, Yi-Min Yan, He-Fan He, Li Yang

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Abstract

Background: Clinical studies have demonstrated that multiple inflammatory related proteins are associated with hypertrophic cardiomyopathy (HCM). However, the precise role of these factors in the pathogenesis of HCM remains uncertain.

Methods: The link between inflammatory related proteins and HCM was analyzed using Mendelian randomization (MR), followed by bioinformatics to explore the role of inflammatory related proteins in HCM. In vivo and in vitro models of HCM were established to elucidate how inflammatory related proteins influence HCM progression.

Results: Our MR analysis revealed a negative correlation between the inflammation related protein CX3CL1 and HCM. Bioinformatics and in vivo data similarly demonstrated a reduction in CX3CL1 expression in HCM. CX3CL1 was found to be mainly expressed in cardiomyocytes and endothelial cells via the Human Protein Atlas database and its' expression in both cells was obviously downregulated after being treated by angiotensin-II. Importantly, functional characteristics and correlation analysis of CX3CL1 indicated that it was most closely associated with macrophages efferocytosis. Consequently, we examined the signature molecules (AXL, MERTK, and TYRO3) associated with efferocytosis, which revealed a significant decrease in their expression in HCM. Notably, recombinant mouse CX3CL1 (rm-CX3CL1) reversed this process.

Conclusions: In conclusion, CX3CL1-meidated impaired efferocytosis plays a critical role in the initiation and development of HCM, and modulation of CX3CL1 may prove advantageous in managing HCM progression.

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基于多组学分析的肥厚性心肌病中内皮细胞来源的cx3cl1介导的巨噬细胞efferocylosis受损

背景：临床研究表明，多种炎症相关蛋白与肥厚性心肌病（HCM）有关。然而，这些因素在HCM发病机制中的确切作用仍不确定。方法：采用孟德尔随机化（Mendelian randomization， MR）方法分析炎症相关蛋白与HCM之间的关系，并结合生物信息学方法探讨炎症相关蛋白在HCM中的作用。建立了HCM的体内和体外模型，以阐明炎症相关蛋白如何影响HCM的进展。结果：我们的MR分析显示炎症相关蛋白CX3CL1与HCM呈负相关。生物信息学和体内数据同样显示了HCM中CX3CL1表达的减少。通过Human Protein Atlas数据库发现CX3CL1主要表达于心肌细胞和内皮细胞，经血管紧张素- ii处理后，CX3CL1在心肌细胞和内皮细胞中的表达均明显下调。重要的是，CX3CL1的功能特征和相关性分析表明，它与巨噬细胞efferocytosis的关系最为密切。因此，我们检查了与efferocytosis相关的特征分子（AXL， MERTK和TYRO3），发现它们在HCM中的表达显著降低。值得注意的是，重组小鼠CX3CL1 （rm-CX3CL1）逆转了这一过程。结论：综上所述，CX3CL1介导的胞浆功能受损在HCM的发生和发展中起着关键作用，CX3CL1的调节可能在控制HCM的进展中具有优势。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Inflammation Research 医学-免疫学

CiteScore

9.90

自引率

1.50%

发文量

134

审稿时长

3-8 weeks

期刊介绍： Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.